JP2010248206A - Microparticle inhalation formulations - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aerosol preparation consisting of medicine fine particles stably suspended in a hydrofluoroalkane propellant as a medicinal product of a pressurized constant amount-administering inhaler. <P>SOLUTION: The aerosol preparation is provided by dispersing medicinal fine particles covered with a cover of one kind or a plurality of kinds of membrane-forming phospholipid and at least one kind of surfactant in 0.1 to 10 micron range mean particle diameter in 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) propellant. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to an aerosol formulation consisting of drug microparticles coated with a lipid membrane and suspended in a hydrofluoroalkane propellant.

Delivery of drugs in pressurized metered-dose inhalers (MDI) currently uses chlorofluorocarbons as propellants. In order to gradually reduce chlorofluorocarbons (which may deplete the ozone layer), products marketed using chlorofluorocarbons are hydrofluoroalkane (HFA) propellants, such as Du Pont Chemicals, Uses 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) marketed by Wilmington, Delaware, USA Then you have to re-specify. The solvent behavior of the proposed alternative propellant is quite different from that of chlorofluorocarbons. For example, there are differences in physicochemical properties such as polarity, vapor pressure, and density, thereby allowing the use of pressurized metered dose inhaler drug products for delivery to the lung using hydrofluoroalkanes as propellants. Development needs have arisen [Byron et al., Resp. Drug Deliv., 4 (1994)].

Numerous patent documents address these differences in physicochemical properties in formulations for inhalers. U.S. Pat. No. 5,492,688 relates to an MDI formulation with more than 90 wt.% HFA 134a, less than 5 wt.% Finely divided drug particles and polyethylene glycol 300, diethylene glycol monoethyl ether, polyoxyethylene 20 sorbitan as a single propellant. Utilizes less than 5% by weight of polar surfactant selected from the group consisting of monooleate, propoxylated polyethylene glycol and polyoxyethylene 4-lauryl ether.

International patent application WO 91/04011 is coated with a single non-perfluorinated surfactant dispersant and suspended in an aerosol propellant, which is substantially insoluble in this propellant. A self-propelled aerosol composition containing a finely divided pre-micronized solid drug that is turbid is described. Suitable dispersants include, among others, various oils, sorbitan oleate, polyoxyethylene sorbitan, lecithin, and polyoxyethylene. The amount of surfactant used keeps as little as possible to avoid particle aggregation and increase particle size.

International patent application 96/19197 relates to a pharmaceutical aerosol formulation comprising: (a) a hydrofluoroalkane propellant, (b) a pharmaceutically active polypeptide dispersible in said propellant and (c) C8. -Includes surfactants that are C16 fatty acids or salts thereof, bile salts, phospholipids or alkyl saccharides, which enhance systemic absorption of the polypeptide in the lower respiratory tract. International patent application 96/19198 by the same inventor relates to a pharmaceutical aerosol formulation, the formulation comprising an HFA propellant, a physiologically effective amount of a drug for inhalation, a C8-C16 fatty acid or salt thereof, a bile salt, Includes surfactants that are phospholipids or alkyl saccharides. Both patent specifications describe a physical mixture of active agent and surfactant in the propellant and do not include a previous encapsulation step.

International Patent Application 96/40089 relates to a pharmaceutical aerosol formulation, wherein the pharmaceutical composition for aerosol delivery contains a drug, a halogenated alkane propellant, and a biocompatible C16 + unsaturated vegetable oil.

International patent application 90/11754 relates to an aerosol formulation, containing an azole antifungal agent as an active ingredient in a form suitable for administration by inhalation.
International patent application 94/21228 relates to a pharmaceutical aerosol formulation, which contains a diol / dioic acid condensate as a dispersant, plus a propellant and a therapeutically effective amount of a particulate drug.

International Patent Application 96/06598 relates to a pharmaceutical composition for aerosol delivery, comprising a drug, a non-chlorofluorocarbon propellant, and a polyglycolized glyceride.

International Patent Application No. 92/06675 relates to aerosol formulations in which a therapeutically effective amount of beclomethasone 17,21 dipropionate, 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1 1,2,3,3,3-heptafluoropropane (HFA 227) propellant or mixture and an amount of ethanol effective to dissolve beclomethasone 17,21 dipropionate in the propellant. All 17,21 beclomethasone dipropionate is substantially dissolved in the formulation and is substantially free of surfactant.

International patent application 93/05765 relates to a pressurized aerosol composition comprising a liquefied hydrofluoroalkane, a dispersible powder drug in the hydrofluoroalkane and a polymer soluble in the liquefied hydrofluoroalkane. This polymer contains amide-containing units or carboxylic acid ester-containing units as repeating structural units.

U.S. Pat. No. 4,174,295 relates to a propellant composition for use in an aerosol, the composition being essentially 5 to 60% by weight CH ₂ F ₂ and CF ₃ − based on the total weight of the propellant composition. The hydrogen-containing fluorocarbon selected from CH ₃ and 40 to 95% by weight of hydrogen-containing chlorofluorocarbon or hydrogen-containing fluorocarbon based on the total weight of the propellant composition, each hydrogen-containing chlorofluorocarbon or hydrogen-containing fluorocarbon being CF ₃ -CHClF, CF ₃ -CH ₂ Cl, CF ₃ -CH ₂ F, CClF ₂ -CF ₃ or CHF ₂ -CH ₃

U.S. Pat.No. 5,118,494 relates to suspension aerosol formulations with 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227) or Contains a propellant comprising a hydrofluorocarbon selected from a mixture, a therapeutically effective amount of a powdered drug, and about 0.001-0.6% by weight of a perfluorinated carboxylic acid or ester as a surfactant dispersant based on the total weight of the formulation . The formulation exhibits virtually no drug crystallization over time, is readily redispersible, and is not fast enough to prevent reproducible administration of the drug upon redispersion.

U.S. Pat.No. 5,126,123 relates to an aerosol inhalant formulation which is suspended in physiologically effective amounts of micronized inhalant and 1,1,1,2-tetrafluoroethane. Consists essentially of 2-tetrafluoroethane soluble, perfluorinated surfactant.

US Pat. No. 5,182,097 relates to an aerosol formulation used to deliver a drug to a patient by inhalation device and includes a propellant composed of 1,1,1,2-tetrafluoroethane alone. The propellant comprises at least 90% by weight aerosol formulation, inhalable drug dispersed or dissolved in the propellant, and the inhalable drug has a split dimension of less than 100 microns in diameter. Inhalable drugs exceed 5% by weight of the aerosol formulation. Oleic acid is used as a surfactant to help disperse the inhalable drug in the propellant, and the oleic acid is less than 0.2% w / v of the aerosol formulation.

US Pat. No. 5,202,110 relates to aerosol formulations for use in metered dose inhalers, pharmaceutically acceptable inhalable propellants, dipropion used as inhalable drugs dispersed or dissolved in propellants Includes inclusion compound or molecular association of acid beclomethasone. The inclusion compound or molecular aggregate of beclomethasone dipropionate is formed with 1,1-dichloro-2,2,2-trifluoroethane or 1,1-dichloro-1-fluoroethane or dimethyl ether, Molecular aggregates are inhalable particle sizes.

U.S. Pat.No. 5,474,759 relates to aerosol formulations and relates to an effective amount of drug, 1.1,1,2,3,3,3-heptafluoropropane (HFA 227), optionally a propylene glycol diester or medium chain of a medium chain fatty acid. It consists essentially of excipients selected from triglyceride esters of fatty acids. Optionally, a surfactant is present with other excipients.

International patent application 96/32150 describes a drug for inhalation consisting of salmeterol, or a physiologically acceptable salt thereof, and a fluorocarbon propellant, optionally one or more other pharmaceutically active agents or one or more excipients. It relates to a metered dose that uses one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, to coat some or all of the internal surface to dispense the formulation.

International Patent Application No. 96/32151 describes fluticasone propionate, or a physiologically acceptable solvate thereof, and a fluorocarbon propellant, optionally one or more other pharmaceutically active agents or one or more additives. A metered dose inhaler comprising one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, to coat some or all of the internal surface to dispense a drug formulation for inhalation comprising a dosage form About.

International Patent Application 96/18384 has 1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) or its propellant as its propellant. It relates to a pharmaceutical aerosol formulation comprising a mixture, 1,1,2,2,3-pentafluoropropane as a copropellant, and a granular drug.

International patent application 94/03153 relates to a pharmaceutical aerosol formulation consisting of particulate beclomethasone dipropionate or an acceptable solvate and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, substantially free of surfactants.

International Patent Application 96/32099 describes an inhalable drug comprising albuterol, or a physiologically acceptable salt thereof, and a fluorocarbon propellant, optionally one or more other pharmaceutically active agents or one or more excipients. The present invention relates to a metered dose inhaler that uses one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, to coat some or all of the internal surface for dispensing the formulation.

International patent application 93/11745 consists of a particulate drug, a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant and a polar cosolvent up to 5% w / w based on the propellant and is substantially free of surfactants It relates to aerosol formulations.

International Patent Application 93/11743 is a pharmaceutical product comprising a particulate drug or physiologically acceptable salt and solvate comprising salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant. It relates to aerosol formulations. The formulation is substantially free of surfactant.

International patent application 93/15741 has a beclomethasone dipropionate monohydrate salt with a particle size of substantially less than 20 microns, crystal water of monohydrate salt plus at least 0.015% w / w based on the formulation. It relates to a pharmaceutical aerosol formulation comprising w water and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

International patent application 93/11744 relates to a pharmaceutical aerosol formulation comprising a particulate drug and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, wherein the drug is salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or a physiologically acceptable salt thereof or When other than the solvate, the formulation is substantially free of surfactant.

In the present invention, it has now surprisingly been found that a particularly stable suspension consisting of fine particles in HFA 134a or HFA 227 is obtained. These microparticles are composed of drug microparticles coated with a phospholipid-containing membrane. Preferably, the drug particles are coated with a mixture of phospholipid (s) that forms a film that wraps outside the microparticles and at least one surfactant. The average particle size of the drug is 100 nm to 10 microns, preferably 0.1 to 10 microns, sonication, or high shear and / or impact phospholipids or other membrane-forming amphiphilic lipids, and preferably at least one By other methods that cause it in the presence of other surfactants. The suspension is then dried to obtain a dry powder. The dried powder of coated particles is conveniently suspended in the propellant. Film-forming components are used to obtain adequate density, polarity and reduction in drug particle aggregation, thus providing good dispersibility and stable drug suspension in the hydrofluorocarbon propellant HFA 134a or HFA 227.

In a preferred embodiment of the present invention, the drug particles are coated with a mixture of phospholipid and at least one surfactant and simultaneously reduced in size so that the average particle size obtained is 0.1 to 10 microns. These excipients are used to adjust the density, polarity and surface tension of drug particles suspended in the propellant. Adjusting the density reduces the tendency of the dispersed particles to become either cream or sediment. The density of the formulation is preferably in the range of 1.0 to 1.5 g / ml to match the density of the HFA propellant. Furthermore, appropriately adjusting the polarity and surface tension of the particles reduces the aggregation of the drug particles, resulting in a readily dispersible and stable drug suspension.

In membrane coating, the weight ratio of phospholipid (s) to surfactant (s) is 0.01-100, preferably 0.02-50, more preferably 0.04-25. Within range. The type and amount of surfactant and co-surfactant used is based on the relative solubility and / or polarity of these components. Therefore, the pharmaceutical composition is optimized for each individual drug. The coating process minimizes the amount of excipients required to select an acceptable formulation.

Importantly, the total amount of surfactant, including phospholipids, is preferably greater than 0.1% and less than 200% based on drug content.

Production method
Sonication method:
Sonication reduces the size of supramolecular drugs and phospholipid structures through the cavitation process. This process breaks down the materials that are propelled together at high speed, creating small cavities that result in crushing and shearing. This can simultaneously break the components into submicron fragments and cover the hydrophobic surface of the microparticles. . In the present invention, the sonication is performed after mixing the drug, phospholipid (one or more), surfactant (one or more) and other additional components (one or more) with a solvent. Sonication was performed using a Sonic Dismembler Model 550 (Fisher Scientific) equipped with a 0.5 inch probe at a controlled temperature of 5-10 ° C., output settings 3-5 for 5-60 minutes, average particle size Repeat until 0.1-5 microns. In order to better control the temperature, sonication is automatically performed with an on / off period of 10 seconds.

The resulting product is then converted to a dry form by freeze drying or spray drying, followed by obtaining a powder that is suspended in HFA 134a or HFA 227.
A method involving high pressure that results in high shear and impact:
The drug and other suitable ingredients are homogenized by high pressure homogenization and / or microfluidization known in the art. In the microfluidization method, high shear is created by the collision of the opposing fine jets of liquid and a collision occurs between the particles and the wall of the fluidizer. In the high pressure homogenization method, a sample is forced into a narrow orifice with high pressure and high shear, and the sample undergoes impact against the wall and rapid depressurization to atmospheric pressure. The product is then made into a dry form by freeze drying or spray drying to obtain a powder that is subsequently suspended in HFA 134a or HFA 227. Sonication and high shear and impact methods are not limited to aqueous media, but can also be performed in volatile organic solvents.

Dimension reduction in air:
Drug crystals can also be reduced in size by high velocity impact in air and subsequently coated with phospholipids and surfactants. The product is then made into a dry form by freeze drying or spray drying to obtain a powder that is subsequently suspended in HFA 134a or HFA 227.

Dimensional reduction due to in-flight crystallization:
A solution of phospholipid, surfactant (s), drug and any additional ingredients in a volatile solvent can be sprayed and the solvent removed by evaporation simultaneously during flight. Collect the dry powder on a smooth surface and suspend it in a kind of propellant.

Size reduction by controlled crystallization method:
For example, by crystallization using a supercritical fluid.
The composition of the present invention contains at least one phospholipid and any at least one surfactant in addition to the active substance.

Examples of suitable phospholipids are saturated or unsaturated forms of diacylphosphatidylcholine, diacylphosphatidylglycerol, diacylphosphatidylethanolamine, diacylphosphatidylinositol and saturated or unsaturated forms of diacylphosphatidylserine and the corresponding lysophospholipids.

Examples of suitable surfactants are: 1. Polyoxyethylene sorbitan fatty acid esters, such as mono- and tri-lauryl, palmityl, stearyl and oleyl esters, such as the product available under the trade name "Tween", known as polysorbate .
2. Polyoxyethylene fatty acid esters, for example, polyoxyethylene stearic acid esters of the known type available under the trade name Myrj, such as Myrj 52.
3. A commercially available product of the type known as polyoxyethylene castor oil derivatives, for example Cremophors. Particularly suitable are polyoxyl 35 castor oil (Cremophor EL) and polyoxyl 40 hydrogenated castor oil (Cremophor RH40).
4. Vitamin E or its derivatives, for example D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS).
5. PEG glyceryl fatty acid esters such as PEG-8 glyceryl caprylate / caprate (commercially known as Labrasol), PEG-4 glyceryl caprylate / caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate (Gelucire 44/14), PEG-6 glyceryl monooleate (Labrafil M 1944 CS), PEG-6 glyceryl linoleate (Labrafil M 2125 CS).
6. Propylene glycol mono- and di-fatty acid esters such as propylene glycol laurate, propylene glycol caprylate / caprate, and diethylene glycol monoethyl ether (commercially known as transcutol).
7. Sorbitan fatty acid esters, for example, known and available under the trade name Span (eg Span 20).
8. A commercially available product known as a polyoxyethylene-polyoxypropylene copolymer, eg, Poloxamer such as Pluronic or Poloxamer 188 NF.
9. Glycerol triacetate 10. Monoglycerides and acetylated monoglycerides such as glycerol monooleate, glyceryl monostearate and mono- and di-acetylated monoglycerides.
11. Bile salts 12. Polyethylene glycol (PEG), eg PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1500, PEG 3400 (known under the trade names Carbowax, Lutrol E and Hodag PEG, commercially available) it can).
13. Substituted cellulose products such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose.
14. Carbomers, known for example under the trademark Carbopol, which are commercially available.

Suitable phospholipids and surfactants are not limited to those described above, but may include any compound that can improve the galenical properties of the formulations of the present invention.
The composition of the present invention can contain other components in addition to the drug, phospholipid (s) and surfactant (s). For example, the composition may additionally include one or more active ingredients, additives or diluents such as pharmaceutically acceptable or inorganic substances, cryoprotectants such as trehalose and mannitol, antioxidants and preservatives. There are agents.

The aerosol formulations of the present invention are useful for local or systemic treatment of disease, including, for example, administration locally or by the nasal route, and can be administered via the upper and lower respiratory tract.

The following illustrates the composition of the present invention, but does not limit the composition.
In the examples below, a microparticle formulation (30 ml scale) was prepared by adding certain components to a suitable solvent and then sonicating. The solvent was then evaporated using, for example, lyophilization.

Next, an appropriate amount of the obtained dry powder was weighed and placed in an aerosol container, and then about 40 ml of HFA 134a was added per container. The container was then shaken by hand for about 1 minute and sonicated for 15-30 minutes in a water bath sonicator and / or overnight on a shaker.

［本発明の態様］
［１］膜形成性両親媒性脂質で被覆され、1,1,1,2-テトラフルオロエタン(HFA 134a)または1,1,1,2,3,3,3-ヘプタフルオロプロパン(HFA 227)プロペラント中に分散されている粒度範囲０．１〜１０ミクロンの薬物微粒子の安定化された粒子から本質的に構成されるエーロゾル製剤。
［２］両親媒性脂質がリン脂質である１に記載のエーロゾル製剤。
［３］リン脂質被覆が少なくとも一種の界面活性剤も含有する２に記載のエーロゾル製剤。
［４］一種またはそれ以上の膜形成性リン脂質と少なくとも一種の界面活性剤で被覆され、HFA 134a または HFA 227プロペラント中に分散されている平均粒度範囲０．１〜１０ミクロンの薬物微結晶から本質的に構成されるエーロゾル製剤であって、被覆した薬物微粒子の密度がプロペラントの密度と実質的に同じであり、薬物微粒子上の被覆の量が薬物の重量を基準に０．１％を超え２００％未満であるエーロゾル製剤。
［５］プロペラントが製剤の少なくとも７０重量％の割合を占める１または４に記載のエーロゾル製剤。
［６］プロペラントが製剤の少なくとも９０重量％の割合を占める５に記載のエーロゾル製剤。
［７］ 薬物が製剤の５重量％未満の割合を占める５に記載のエーロゾル製剤。
［８］界面活性剤に対するリン脂質の重量比が０．０４〜２５の範囲である３または４に記載のエーロゾル製剤。
［９］界面活性剤に対するリン脂質の重量比が０．０２〜５０の範囲である３または４に記載のエーロゾル製剤。
［１０］界面活性剤に対するリン脂質の比が０．０１〜１００；好ましくは０．０２〜５０；より好ましくは０．０４〜２５の範囲である。
［１１］リン脂質が製剤の２０重量％未満の割合を占める２または４に記載のエーロゾル。
［１２］リン脂質が製剤の５重量％未満の割合を占める２に記載のエーロゾル。
［１３］界面活性剤が製剤の２０重量％未満の割合を占める３に記載のエーロゾル。
［１４］界面活性剤が製剤の５重量％未満の割合を占める３または４に記載のエーロゾル。
［１５］HFA134a、HFA227またはそれらの混合物から選択される非水性プロペラント中に懸濁している平均粒度が０．１〜１０ミクロンの薬物微粒子からなるエーロゾル製剤を含有する定量投与用吸入器であって、前記薬物微粒子が膜形成性両親媒脂質でおよび場合によりさらに界面活性剤で被覆され、凝集に対し安定化されている定量投与用吸入器。
［１６］薬物粒子がリン脂質で被覆される１５に記載の吸入器。
［１７］リン脂質被覆が界面活性剤も含有する１５または１６に記載の吸入器。
［１８］リン脂質と少なくとも一種の界面活性剤との混合物で被覆され、HFA 134a または HFA 227プロペラント中に分散されている平均粒度範囲０．１〜１０ミクロンの薬物微粒子から本質的に構成されるエーロゾル製剤を含有する定量投与用吸入器であって、被覆した薬物微結晶の密度がプロペラントの密度と実質的に同じであり、薬物微粒子上の被覆の量が薬物の重量を基準に０．１％を超え２００％未満であるエーロゾル製剤。
［１９］膜形成性両親媒脂質と場合により界面活性剤とで被覆され、上気道または低気道に送達するための薬学的に許容できるキャリアー中に分散されている粒度範囲が０．１〜１０ミクロンの薬物微粒子。
［２０］上気道または下気道に送達するための、膜形成性両親媒脂質と場合により界面活性剤とで被覆され、０．１〜１０ミクロンの粒度範囲の薬物微粒子から本質的に構成される乾燥粉末。
［２１］少なくとも一種の膜形成性リン脂質と少なくとも一種の界面活性剤の包みで被覆され、1,1,1,2-テトラフルオロエタン(HFA 134a)または1,1,1,2,3,3,3-ヘプタフルオロプロパン(HFA 227)プロペラント中に分散されている平均粒度範囲０．１〜１０ミクロンの薬物微結晶から本質的に構成される乾燥懸濁物エーロゾル製剤であって、被覆した薬物微粒子の密度がプロペラントの密度と実質的に同じであり、薬物微粒子上の被覆の量が薬物の重量を基準に０．１％を超え２００％未満であるエーロゾル製剤。
［２２］リン脂質被覆が少なくとも一種の界面活性剤も含有する１に記載のエーロゾル製剤。
［２３］プロペラントが製剤の少なくとも７０重量％の割合を占める１に記載のエーロゾル製剤。
［２４］プロペラントが製剤の少なくとも９０重量％の割合を占める３に記載のエーロゾル製剤。
［２５］ 薬物が製剤の５重量％未満の割合を占める３に記載のエーロゾル製剤。
［２６］界面活性剤に対するリン脂質の重量比が０．０４〜２５の範囲である１に記載のエーロゾル製剤。
［２７］界面活性剤に対するリン脂質の重量比が０．０２〜５０の範囲である１に記載のエーロゾル製剤。
［２８］界面活性剤に対するリン脂質の比が０．０１〜１００の範囲である１に記載のエーロゾル製剤。
［２９］リン脂質が製剤の２０重量％未満の割合を占める１に記載のエーロゾル。
［３０］リン脂質が製剤の５重量％未満の割合を占める１に記載のエーロゾル。
［３１］界面活性剤が製剤の２０重量％未満の割合を占める１に記載のエーロゾル。
［３２］界面活性剤が製剤の５重量％未満の割合を占める１に記載のエーロゾル。
［３３］少なくとも一種の膜形成性リン脂質と少なくとも一種の界面活性剤との混合物で被覆され、1,1,1,2-テトラフルオロエタン(HFA 134a)または1,1,1,2,3,3,3-ヘプタフルオロプロパン(HFA 227)プロペラント中に分散されている平均粒度範囲０．１〜１０ミクロンの安定化された薬物微結晶から本質的に構成されるエーロゾル製剤を含有する定量投与用吸入器であって、該製剤が１．０〜１．５ｇ／ｍｌの範囲の密度を有し、被覆した薬物微粒子の密度がプロペラントの密度と実質的に同じであり、薬物微粒子上の被覆の量が薬物の重量を基準に０．１％を超え２００％未満である、定量投与用吸入器。
［３４］界面活性剤に対するリン脂質の比が０．０４〜２５の範囲である８に記載のエーロゾル製剤。
［３５］少なくとも一種の膜形成性リン脂質と少なくとも一種の界面活性剤の包みで被覆され、上気道または下気道に送達するための、薬学的に許容できるキャリアー中に分散されている粒度範囲が０．１〜１０ミクロンの安定化された薬物微粒子から本質的に構成される、１．０〜１．５ｇ／ｍｌの範囲の密度を有する薬物微粒子であって、薬物微粒子上の被覆の量が薬物の重量を基準に０．１％を超え２００％未満である、薬物微粒子。
［３６］少なくとも一種の膜形成性リン脂質と少なくとも一種の界面活性剤の包みで被覆された、粒度範囲が０．１〜１０ミクロンの安定化された薬物微粒子から本質的に構成される、１．０〜１．５ｇ／ｍｌの範囲の密度を有する乾燥粉末であって、薬物微粒子上の被覆の量が薬物の重量を基準に０．１％を超え２００％未満である、乾燥粉末。
［３７］一種またはそれ以上の膜形成性リン脂質と少なくとも一種の界面活性剤で被覆され、1,1,1,2-テトラフルオロエタン(HFA 134a)または1,1,1,2,3,3,3-ヘプタフルオロプロパン(HFA 227)プロペラント中に分散されている粒度範囲０．１〜１０ミクロンの安定化された薬物微粒子から本質的に構成され、
該界面活性剤が、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンひまし油誘導体、ビタミンEおよびその誘導体、ポリオキシエチレングルコールグリセリル脂肪酸エステル、プロピレングリコールモノ−およびジ−脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレン−ポリオキシプロピレンコポリマー、グリセロールトリアセテート、モノグリセライドおよびアセチル化モノグリセライド、胆汁酸塩、ポリエチレングリコール、置換セルロース製品、カルボマーより成る群から選択され、
被覆した薬物微粒子の密度がプロペラントの密度と実質的に同じであり、
薬物微粒子上の被覆の量が薬物の重量を基準に０．１％を超え２００％未満であるエーロゾル製剤。
［３８］ポリオキシエチレン脂肪酸エステルがポリオキシエチレンステアリン酸エステルであり、ポリオキシエチレンひまし油誘導体がポリオキシル３５ひまし油又はポリオキシル４０水素化ひまし油であり、ビタミンＥ誘導体がD-α-トコフェリルポリエチレングリコール1000 サクシネート であり、置換セルロースがヒドロキシプロピルセルロースである、３７のエロゾール製剤。

[Aspect of the Invention]
[1] Coated with a film-forming amphiphilic lipid, 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227 ) An aerosol formulation consisting essentially of stabilized particles of drug microparticles in the particle size range 0.1-10 microns dispersed in a propellant.
[2] The aerosol formulation according to 1, wherein the amphiphilic lipid is a phospholipid.
[3] The aerosol formulation according to 2, wherein the phospholipid coating also contains at least one surfactant.
[4] Drug crystallites having an average particle size range of 0.1 to 10 microns coated with one or more film-forming phospholipids and at least one surfactant and dispersed in HFA 134a or HFA 227 propellant Wherein the density of the coated drug microparticles is substantially the same as the density of the propellant and the amount of coating on the drug microparticles is 0.1% based on the weight of the drug An aerosol formulation that is greater than and less than 200%.
[5] The aerosol formulation according to 1 or 4, wherein the propellant accounts for at least 70% by weight of the formulation.
[6] The aerosol formulation according to 5, wherein the propellant accounts for at least 90% by weight of the formulation.
[7] The aerosol formulation according to 5, wherein the drug accounts for less than 5% by weight of the formulation.
[8] The aerosol formulation according to 3 or 4, wherein the weight ratio of phospholipid to surfactant is in the range of 0.04 to 25.
[9] The aerosol formulation according to 3 or 4, wherein the weight ratio of phospholipid to surfactant is in the range of 0.02 to 50.
[10] The ratio of phospholipid to surfactant is in the range of 0.01 to 100; preferably 0.02 to 50; more preferably 0.04 to 25.
[11] The aerosol according to 2 or 4, wherein the phospholipid accounts for less than 20% by weight of the preparation.
[12] The aerosol according to 2, wherein the phospholipid accounts for less than 5% by weight of the preparation.
[13] The aerosol according to 3, wherein the surfactant accounts for less than 20% by weight of the preparation.
[14] The aerosol according to 3 or 4, wherein the surfactant accounts for less than 5% by weight of the preparation.
[15] A metered dose inhaler comprising an aerosol formulation consisting of fine drug particles having an average particle size of 0.1 to 10 microns suspended in a non-aqueous propellant selected from HFA134a, HFA227 or a mixture thereof. A metered dose inhaler wherein the drug microparticles are coated with a film-forming amphiphilic lipid and optionally further coated with a surfactant and stabilized against aggregation.
[16] The inhaler according to 15, wherein the drug particles are coated with phospholipid.
[17] The inhaler according to 15 or 16, wherein the phospholipid coating also contains a surfactant.
[18] Consisting essentially of drug microparticles with an average particle size range of 0.1 to 10 microns coated with a mixture of phospholipid and at least one surfactant and dispersed in HFA 134a or HFA 227 propellant. A metered dose inhaler containing an aerosol formulation wherein the density of the coated drug microcrystals is substantially the same as the density of the propellant and the amount of coating on the drug microparticles is 0 based on the weight of the drug. An aerosol formulation that is greater than 1% and less than 200%.
[19] A particle size range of 0.1 to 10 coated with a film-forming amphiphilic lipid and optionally a surfactant and dispersed in a pharmaceutically acceptable carrier for delivery to the upper or lower respiratory tract. Micron drug particles.
[20] Essentially composed of drug microparticles with a particle size range of 0.1-10 microns coated with a film-forming amphiphilic lipid and optionally a surfactant for delivery to the upper or lower respiratory tract Dry powder.
[21] covered with a packet of at least one film-forming phospholipid and at least one surfactant, and 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3, A dry suspension aerosol formulation consisting essentially of drug microcrystals with an average particle size range of 0.1 to 10 microns dispersed in 3,3-heptafluoropropane (HFA 227) propellant comprising a coating The aerosol formulation wherein the density of the drug microparticles is substantially the same as the density of the propellant and the amount of coating on the drug microparticles is greater than 0.1% and less than 200% based on the weight of the drug.
[22] The aerosol formulation according to 1, wherein the phospholipid coating also contains at least one surfactant.
[23] The aerosol formulation according to 1, wherein the propellant accounts for at least 70% by weight of the formulation.
[24] The aerosol preparation according to 3, wherein the propellant accounts for at least 90% by weight of the preparation.
[25] The aerosol formulation according to 3, wherein the drug accounts for less than 5% by weight of the formulation.
[26] The aerosol formulation according to 1, wherein the weight ratio of phospholipid to surfactant is in the range of 0.04 to 25.
[27] The aerosol formulation according to 1, wherein the weight ratio of phospholipid to surfactant is in the range of 0.02 to 50.
[28] The aerosol formulation according to 1, wherein the ratio of phospholipid to surfactant is in the range of 0.01-100.
[29] The aerosol according to 1, wherein the phospholipid accounts for less than 20% by weight of the preparation.
[30] The aerosol according to 1, wherein the phospholipid accounts for less than 5% by weight of the preparation.
[31] The aerosol according to 1, wherein the surfactant accounts for less than 20% by weight of the preparation.
[32] The aerosol according to 1, wherein the surfactant accounts for less than 5% by weight of the preparation.
[33] coated with a mixture of at least one membrane-forming phospholipid and at least one surfactant, and 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3 Quantitatively Containing an Aerosol Formulation Consisting of Stabilized Drug Microcrystals with an Average Particle Size Range of 0.1 to 10 Micron Dispersed in 1,3,3-Heptafluoropropane (HFA 227) Propellant An inhaler for administration, wherein the formulation has a density in the range of 1.0 to 1.5 g / ml, and the density of the coated drug microparticles is substantially the same as the density of the propellant; The metered dose inhaler, wherein the amount of coating is greater than 0.1% and less than 200% based on the weight of the drug.
[34] The aerosol formulation according to 8, wherein the ratio of phospholipid to surfactant is in the range of 0.04 to 25.
[35] A particle size range coated with a packet of at least one film-forming phospholipid and at least one surfactant and dispersed in a pharmaceutically acceptable carrier for delivery to the upper or lower respiratory tract. Drug microparticles having a density in the range of 1.0 to 1.5 g / ml consisting essentially of stabilized drug microparticles of 0.1 to 10 microns, wherein the amount of coating on the drug microparticles Drug microparticles that are greater than 0.1% and less than 200% based on the weight of the drug.
[36] consisting essentially of stabilized drug microparticles having a particle size range of 0.1 to 10 microns, coated with at least one membrane-forming phospholipid and at least one surfactant wrap A dry powder having a density in the range of 0 to 1.5 g / ml, wherein the amount of coating on the drug microparticles is greater than 0.1% and less than 200% based on the weight of the drug.
[37] coated with one or more film-forming phospholipids and at least one surfactant, 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3, Consisting essentially of stabilized drug microparticles in the particle size range 0.1-10 microns dispersed in 3,3-heptafluoropropane (HFA 227) propellant;
The surfactant is polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene castor oil derivative, vitamin E and its derivatives, polyoxyethylene glycol glyceryl fatty acid ester, propylene glycol mono- and di-fatty acid ester, Selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene copolymers, glycerol triacetate, monoglycerides and acetylated monoglycerides, bile salts, polyethylene glycols, substituted cellulose products, carbomers,
The density of the coated fine drug particles is substantially the same as the density of the propellant,
An aerosol formulation wherein the amount of coating on the drug microparticles is greater than 0.1% and less than 200% based on the weight of the drug.
[38] The polyoxyethylene fatty acid ester is polyoxyethylene stearate, the polyoxyethylene castor oil derivative is polyoxyl 35 castor oil or polyoxyl 40 hydrogenated castor oil, and the vitamin E derivative is D-α-tocopheryl polyethylene glycol 1000 succinate. 37, the aerosol formulation of 37, wherein the substituted cellulose is hydroxypropylcellulose.

Claims (1)

Coated with one or more membrane-forming phospholipids and at least one surfactant encapsulated, 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3, A dry suspension aerosol formulation consisting essentially of stabilized drug microcrystals with an average particle size range of 0.1 to 10 microns dispersed in 3,3-heptafluoropropane (HFA 227) propellant. The formulation has a density in the range of 1.0 to 1.5 g / ml, the density of the coated drug microparticles is substantially the same as the density of the propellant, and the amount of coating on the drug microparticles Aerosol formulation in which is greater than 0.1% and less than 200% based on the weight of the drug.